Neuropathologies mediating the behavioral (e.g., self-injurious behavior) and cognitive dysfunctions of persons with Lesch-Nyhan disease (LND) e.g., "irreversible" depletions of striatal dopamine and its metabolites) and microcephaly (M; e.g., "irreversible" hippocampal hypoplasia) can be modeled respectively by adult, neonatally 6-hydroxydopamine (6HD)-treated rats and adult rats made micro[en]cephalic using prenatal methylazoxymethanol (MAM) exposure. Our initial and replicated observations were the first to demonstrate that those "irreversible" conditions are reversible in rats, and that reversals can be induced merely with prolonged relatively complex operant learning regimens (Fixed-Ratio [FR] discrimination training procedures). The original submission's review stated that "These findings are sufficiently important to warrant a program of research more specifically devoted to them. Such basic research would have implications for several sciences, including the most basic neurosciences. Its implication for all applied sciences that deal with CNS damage in its many forms should be clear. It is especially exciting that relatively simple, but elegant, operant training procedures should alter indices of brain function so greatly." The broad, long-term objectives of the research described in this revised application are to identify the mechanisms, functional significance, age- dependency, and species and neuropathological generality of our findings. Specifically, in keeping with our goals and those of the previous reviewers, in the present application we aim to: evaluate the relative rates and efficacies with which various FR discrimination training procedures reverse brain-regional dopamine and metabolite depletion in the LND model; compare of the effects of incremental FR discrimination, FR1vFR16 discrimination and FR16 simple-schedule training and performance on brain regional dopamine and metabolite concentrations in adult rats depleted of these substances as adults - a rat Parkinson's disease model; determine FR discrimination training-induced changes in various indices of the density and distribution of dopaminergic neurons and receptors as well as in functional dopamine receptor responsiveness in LM) rats; and evaluate the effects of non-incremental FR discrimination training and FR discrimination performance training on hippocampal weight, synaptic connections and cell-type composition in adult, MAM-induced microencephalic rats. The proposed research could lead to replacement or reduction of drug and surgical (e.g., fetal brain tissue transplants) use by behavioral therapy for some forms of brain damage and their sequelae.